The renin-angiotensin system (RAS) plays a key role in the pathogenesis of chronic kidney injury. Clinical trials with RAS inhibitors suggest angiotensin II (Ang II) may promote renal injury through blood pressure- independent effects. Activation of the immune system by the RAS has been suggested as one mechanism mediating these actions. We have found that chronic infusion of Ang II causes significant kidney injury, infiltration of CD4+ T helper lymphocytes into the kidney, and enhanced expression of pro-inflammatory cytokines including interferon-g (IFN-g) and tumor necrosis factor-a (TNF-a). Administration of the broadly acting immunosuppressive agent mycyophenolate mofetil (MMF) abrogated these effects without affecting blood pressure. Accordingly, we hypothesize that activation of a CD4+ T cell-dependent cellular immune response by Ang II contributes to chronic kidney damage in this setting. Typically, CD4+ T cells do not directly mediate cytotoxic tissue injury. Rather, they regulate immune responses by differentiating into type 1 (Th1) or type 2 (Th2) CD4+ T helper cells. Whereas Th2 cells regulate antibody responses, Th1 cells secrete IFN-g leading to activation of macrophages and cytotoxic CD8+ T cells to mediate cellular damage. Activated macrophages in turn produce TNF-a, which further stimulates Th1 cells. We therefore suggest that Ang II acting through type I angiotensin (AT1) receptors promotes the development of a Th1 immune response in the kidney, with enhanced production of IFN-g and TNF-a leading directly to progressive kidney disease through blood pressure-independent mechanisms. To test this, we will examine Ang II-induced kidney injury in mouse lines with genetic modifications impacting: transcription factors critical for Th1 differentiation, key Th1 cytokines, and AT1 receptor responses in key cell lineages. In addition to CD4+ T cells, IFN-g and TNF-a are expressed by several immune cell lineages and even by renal parenchymal cells. Therefore, we have designed experiments to identify the cellular sources of these cytokines in Ang II- dependent kidney injury. Understanding how Th1 immune responses influence Ang II-induced renal damage should lead to more effective strategies for preventing progressive chronic kidney disease.